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Sphingosine Kinase as an Oncogene: Autocrine Sphingosine 1-Phoshate Modulates ML-1 Thyroid Carcinoma Cell Migration by a Mechanism Dependent on Protein Kinase C- and ERK1/2

Departments of Biology (Cell Biology) (N.B., C.L., C.A., S.B., K.T.) and Biochemistry and Pharmacy (J.H., J.P.S., A.H.), Åbo Akademi University, and Turku Graduate School of Biomedical Sciences (N.B.), 20520 Turku, Finland; The Minerva Foundation Institute for Medical Research (N.B., K.T.), 00290 Helsinki, Finland; and Institute of Biomedicine/Anatomy (T.B.), University of Helsinki, 00250 Helsinki, Finland

Address all correspondence and requests for reprints to: Dr. Kid Törnquist, Department of Biology, Åbo Akademi University, BioCity, Tykistökatu 6, 20520 Turku, Finland. E-mail: ktornqvi{at}abo.fi.

Sphingosine 1-phosphate (S1P) induces migration of the human thyroid follicular carcinoma cell line ML-1 by activation of S1P₁ and S1P₃ receptors, G_i proteins, and the phosphatidylinositol 3-kinase-Akt pathway. Because sphingosine kinase isoform 1 (SK) recently has been implicated as an oncogene in various cancer cell systems, we investigated the functions of SK in the migration, proliferation and adhesion of the ML-1 cell line. SK overexpressing ML-1 cells show an enhanced secretion of S1P, which can be attenuated, by inhibiting SK activity and a multidrug-resistant transport protein (ATP-binding cassette transporter). Furthermore, overexpression of SK enhances serum-induced migration of ML-1 cells, which can be attenuated by blocking ATP-binding cassette transporter and SK, suggesting that the migration is mediated by autocrine signaling through secretion of S1P. Inhibition of protein kinase C, with both small interfering RNA (siRNA) and small molecular inhibitors attenuates migration in SK overexpressing cells. In addition, SK-overexpressing cells show an impaired adhesion, slower cell growth, and an up-regulation of ERK1/2 phosphorylation, as compared with cells expressing a dominant-negative SK. Taken together, we present evidence suggesting that SK enhances migration of ML-1 cells by an autocrine mechanism and that the S1P-evoked migration is dependent on protein kinase C, ERK1/2, and SK.

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